11-13492587-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3PP5_Moderate
The NM_000315.4(PTH):c.166C>T(p.Arg56Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_000315.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251166Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135752
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727232
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74314
ClinVar
Submissions by phenotype
not provided Pathogenic:1
The R56C variant in the PTH gene has been reported previously in the homozygous state in three siblings with biochemical findings consistent with hypoparathyroidism, one of whom exhibited clinical features including muscle cramps and seizures (Lee et al., 2015). Functional studies demonstrate that the R56C variant results in decreased binding to the PTH1R receptor (Lee et al., 2015). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R56C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species. We interpret R56C as a likely pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at